In Vitro Evaluation of Novel Nitazoxanide Derivatives against <i>Mycobacterium tuberculosis</i>

Abstract

Nitazoxanide has antiparasitic and antibiotic activities including activity against <i>Mycobacterium tuberculosis</i>. We prepared and evaluated a set of its analogues to determine the structure-activity relationship, and identified several amide- and urea-based analogues with low micromolar activity against <i>M. tuberculosis</i> in vitro. Pharmacokinetics in the rat suggested a path forward to obtain bioavailable compounds. The series had a good microbiological profile with bactericidal activity in vitro against replicating and nonreplicating <i>M. tuberculosis</i>. Analogues had limited activity against other Gram-positive bacteria but no activity against Gram-negative bacteria. Our studies identified the key liability in this series as cytotoxicity. Future work concentrating on identifying the target(s) could assist in removing activity against eukaryotic cells.